TNF and Hypercalcemia: Other humoral factors that have also been associated with hypercalcemia in RCC include IL-6, IL-1, TNFα, transforming growth factor-alpha and beta, and prostaglandins.13,14 IL-6 has been shown to activate osteoclastic bone resorption but it is unclear whether this cytokine causes hypercalcemia directly or by the effect of PTHrP.